Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification

中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化

基本信息

批准号：
10267729
负责人：
Benjamin Levi
金额：
$ 37.74万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10267729
关键词：
Activities of Daily Living Address Affect Animal Model Anti-Inflammatory Agents Automobile Driving Biological Markers Blood Burn injury Cells Clinical Complex DNA DNA receptor Data Data Set Diagnosis Disease Event Excision FDA approved Goals Heterotopic Ossification Histologic Histones Human Hydroxychloroquine Image Incidence Infection prevention Inflammation Inflammatory Injury Innate Immune Response Internet Intervention Joints Kidney Laboratories Liver Mechanics Mediating Molecular Target Motion Movement Mus Myelogenous Neutrophilic Infiltrate Operative Surgical Procedures Outcome Pathologic Pathway interactions Patient Selection Patients Peroxidases Pharmacology Phenotype Physicians Play Process Prophylactic treatment Radiation Recurrence Reporting Risk Role Secondary to Severities Signal Transduction Site Standardization Stimulus Structure TLR9 gene Therapeutic Time Tissues Treatment Protocols Work bone cell free DNA cohort extracellular high risk hip replacement arthroplasty in vivo inhibitor/antagonist limb injury mouse model musculoskeletal injury neutrophil novel novel therapeutic intervention personalized care personalized medicine prevent prophylactic recruit targeted treatment tissue injury transcriptome transcriptomics treatment strategy wound

项目摘要

Project Summary Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone that occurs in ~20% of patients after hip arthroplasty, musculoskeletal trauma or burns, whereas this incidence increases to over 80% in patients with high energy injuries implicating the role of the innate immune response. Standardized treatment protocols to prevent HO are missing and surgical resection of HO fails to restore pre-injury functional capacity and has a high risk of recurrence. HO, regardless of the inciting event, most commonly forms at sites of mobility. Once HO is diagnosed, physicians restrict movement of the effected joint to limit progression, however, the mechanism behind limiting mobility to alter inflammation and HO progression remains unknown. Further complicating treatment is the fact that there are currently no biomarkers to guide clinicians on which patients are at high HO risk and therefore should receive prophylaxis and when to initiate treatment. Thus, there is a substantial clinical need to develop an effective, inflammatory targeted HO therapy and to validate a biomarker to guide patient selection and precise therapeutic timing. This proposal will generate data sets for those two unmet clinical needs to provide a breakthrough towards more efficient intervention for HO. Recent novel dynamic analyses of HO injuries by our group have identified neutrophil phenotype as central to HO. Specifically, we found that structural components released by neutrophils, known as neutrophil extracellular traps (NETs), play a critical role in HO. This is a novel aspect how the innate immune response contributes to HO. It is reported that tissue injury prompts formation of NETs for prevention of infections (primary NETosis). HO is unique as it forms in sites of mobility which adds a unique force (extrinsic) placed on NETs which has not been studied. Preliminary data demonstrates that motion of a joint disrupts primary NETs to induce propagation of NETs (secondary NETosis), critical to develop HO. We found this HO-specific novel mechanism is mediated by toll-like receptor 9 (TLR9), a known receptor for DNA complexes. Therefore, we propose that TLR9 is a novel target specific to HO. Aim 1: Evaluate the role of NETs as a biomarker to predict HO formation. We will evaluate differential NET formation in HO compared to non-HO control in our mouse models and in a well characterized human patient cohort at risk for HO (hip arthroplasty) to examine injury site and systemic NET levels as a HO biomarker. Aim 2: Characterize the role and therapeutic potential specific to secondary NET formation through TLR9 signaling in HO formation and progression. We will also assess the ability of pharmacologic TLR9 inhibition and neutrophil specific Tlr9 deletion to mitigate secondary NETosis and HO in proven mouse models.

项目概要异位骨化 (HO) 是骨骼外骨的病理形成，约 20% 的人发生髋关节置换术、肌肉骨骼创伤或烧伤后的患者，而这种发生率增加至 80% 以上涉及先天免疫反应作用的高能量损伤患者。标准化缺乏预防 HO 的治疗方案，并且手术切除 HO 未能恢复损伤前的功能容量大，复发风险高。 HO，无论煽动事件如何，最常见于现场形成的流动性。一旦诊断出 HO，医生就会限制受影响关节的运动以限制进展，然而，限制活动性以改变炎症和 HO 进展的机制仍不清楚。使治疗更加复杂的是，目前没有生物标记物可以指导临床医生进行哪些治疗患者处于 HO 高风险，因此应接受预防并确定何时开始治疗。因此，临床迫切需要开发一种有效的炎症靶向 HO 疗法并验证指导患者选择和精确治疗时机的生物标志物。该提案将生成数据集这两个未满足的临床需求为更有效地干预 HO 提供了突破。我们小组最近对 HO 损伤进行的新颖动态分析已确定中性粒细胞表型是核心到何。具体来说，我们发现中性粒细胞释放的结构成分，称为中性粒细胞细胞外陷阱（NET）在 HO 中发挥着关键作用。这是先天免疫反应如何进行的一个新方面对 HO 做出贡献。据报道，组织损伤促进NETs的形成以预防感染（原发性网络病）。 HO 是独特的，因为它在移动部位形成，这增加了施加在其上的独特力（外在力） NET尚未研究过。初步数据表明关节的运动会扰乱初级网络诱导 NET 的传播（继发性 NETosis），这对于形成 HO 至关重要。我们找到了一本HO特有的小说该机制由 Toll 样受体 9 (TLR9) 介导，TLR9 是一种已知的 DNA 复合物受体。因此，我们提出 TLR9 是 HO 特异性的新靶点。目标 1：评估 NET 作为预测 HO 形成的生物标志物的作用。我们将评估差分NET 在我们的小鼠模型和特征明确的人类患者中，与非 HO 对照相比，HO 的形成存在 HO（髋关节置换术）风险的队列，以检查损伤部位和全身 NET 水平作为 HO 生物标志物。目标 2：通过 TLR9 表征继发性 NET 形成的特定作用和治疗潜力 HO 形成和进展中的信号传导。我们还将评估药理 TLR9 抑制的能力中性粒细胞特异性 Tlr9 缺失可减轻经过验证的小鼠模型中的继发性 NETosis 和 HO。